Long noncoding RNA lncPostn links TGF-ß and p53 signaling pathways to transcriptional regulation of cardiac fibrosis.

Cardiac fibroblasts are essential for the homeostasis of the extracellular matrix, whose remodeling in many cardiovascular diseases leads to fibrosis. Long noncoding RNAs (lncRNAs) are associated with cardiac pathologies, but their functions in cardiac fibroblasts and contributions to cardiac fibrosis remain unclear. Here, we aimed to identify fibroblast-enriched lncRNAs essential in myocardial infarction (MI)-induced fibrosis and explore the molecular mechanisms responsible for their functions. Global lncRNA profiling was performed in post-MI mouse heart ventricles and transforming growth factor-ß (TGF-ß)-treated primary cardiac fibroblasts and confirmed in published data sets. We identified the cardiac fibroblast-enriched lncPostn, whose expression is stimulated in cardiac fibrosis induced by MI and the extracellular growth factor TGF-ß. The promoter of lncPostn contains a functional TGF-ß response element, and lncPostn knockdown suppresses TGF-ß-stimulated cardiac fibroblast activation and improves cardiac functions post-MI. LncPostn stabilizes and recruits EP300 to the profibrotic periostin's promoter, representing a major mechanism for its transcriptional activation. Moreover, both MI and TGF-ß enhance lncPostn expression while suppressing the cellular growth gatekeeper p53. TGF-ß and p53 knockdown-induced profibrotic gene expression and fibrosis occur mainly through lncPostn and show additive effects. Finally, levels of serum lncPostn are significantly increased in patients' postacute MI and show a strong correlation with fibrosis markers, revealing a potential biomarker of cardiac fibrosis. Our findings identify the fibroblast-enriched lncPostn as a potent profibrotic factor, providing a transcriptional link between TGF-ß and p53 signaling pathways to regulate fibrosis in cardiac fibroblasts.NEW & NOTEWORTHY Cardiac fibroblasts are essential for the homeostasis of the extracellular matrix, whose remodeling in many cardiovascular diseases leads to fibrosis. Long noncoding RNAs are functional and contribute to the biological processes of cardiovascular development and disorders. Our findings identify the fibroblast-enriched lncPostn as a potent profibrotic factor and demonstrate that serum lncPostn level may serve as a potential biomarker of human cardiac fibrosis postacute myocardial infarction.

Global Analysis of 2-Hydroxy Fatty Acids by Gas Chromatography-Tandem Mass Spectrometry Reveals Species-Specific Enrichment in Echinoderms.

Abnormal levels of 2-hydroxy fatty acids (2-OH FAs) are characterized in multiple diseases, and their quantification in foodstuffs is critical to identify the sources of supplementation for potential treatment. However, due to the structural complexity and limited available standards, the comprehensive profiling of 2-OH FAs remains an ongoing challenge. Herein, an innovative approach based on gas chromatography-tandem mass spectrometry (GC-MS/MS) was developed to determine the full profile of these FA metabolites. MS and MS/MS spectra of the trimethylsilyl (TMS) derivatives of 2-OH fatty acid methyl esters (FAMEs) were collected for peak annotation by their signature fragmentation patterns. The structures were further confirmed by validated structure-dependent retention time (RT) prediction models, taking advantage of the correlation between the RT, carbon chain length, and double bond number from commercial standards and pseudostandards identified in the whole-brain samples from mice. An in-house database containing 50 saturated and monounsaturated 2-OH FAs was established, which is expandible when additional molecular species with different chain lengths and backbone structures are identified in the future. A quantitation method was then developed by scheduled multiple reaction monitoring (MRM) and applied to investigate the profiling of 2-OH FAs in echinoderms. Our results revealed that the levels of total 2-OH FAs in sea cucumber Apostichopus japonicas (8.40 ± 0.28 mg/g dry weight) and starfish Asterias amurensis (7.51 ± 0.18 mg/g dry weight) are much higher than that in sea urchin Mesocentrotus nudus (531 ± 108 µg/g dry weight). Moreover, 2-OH C24:1 is the predominant molecular species accounting for 67.9% of the total 2-OH FA in sea cucumber, while 2-OH C16:0 is the major molecular species in starfish. In conclusion, the current innovative GC-MS approach has successfully characterized distinct molecular species of 2-OH FAs that are highly present in sea cucumbers and starfish. Thus, these findings suggest the possibility of developing future feeding strategies for preventing and treating diseases associated with 2-OH FA deficiency.

Characterization of drinking groundwater quality in rural areas of Inner Mongolia and assessment of human health risks.

Groundwater is an important natural resource of drinking water in rural areas in Inner Mongolia, China. In this study, 4438 drinking groundwater samples were collected from the rural areas of 81 counties in Inner Mongolia, and were analyzed for 16 parameters, including pH, total hardness (TH), chemical oxygen demand (COD), total dissolved solids (TDS), sulfate (SO42-), chloride (Cl-), fluoride (F-), iron (Fe), manganese (Mn), arsenic (As), cadmium (Cd), hexavalent chromium (Cr), lead (Pb), aluminum (Al), cuprum (Cu), zinc (Zn). The groundwater quality was evaluated with water quality index (WQI) and human health risk assessment (HRA). Monte Carlo simulation were applied for the uncertainty and sensitivity analysis in the health risk assessment. The spatial map was employed based on the inverse distance weighted (IDW) interpolation technique. The results reveal that while the hazard quotient (HQ) suggests that the risk of single element contamination is feeble, the hazard index (HI) indicates a potential health risk for the local population. The observed cumulative carcinogenic risk (CCR) indicates a probable risks of carcinogenic health hazards in the study area. The sensitivity analysis revealed that daily ingestion rate (IR), exposure frequency (EF), and the concentrations of As, Mn, F-, and Cr are the most influential parameters for health hazards. The highly polluted areas are mainly distributed in the central and western regions of Inner Mongolia, including Xianghuangqi, New Barag Zuoqi, and Togtoh. It is observed that the groundwater may cause a potential health risk after long-term ingestion. The results of this study will contribute to groundwater management and protection in Inner Mongolia.

2-Hydroxylation of Fatty Acids Represses Colorectal Tumorigenesis and Metastasis via the YAP Transcriptional Axis.

Alteration in lipid composition is an important metabolic adaptation by cancer cells to support tumorigenesis and metastasis. Fatty acid 2-hydroxylase (FA2H) introduces a chiral hydroxyl group at the second carbon of fatty acid (FA) backbones and influences lipid structures and metabolic signaling. However, the underlying mechanisms through which FA 2-hydroxylation is coupled to metabolic adaptation and tumor growth remain elusive. Here, we show that FA2H regulates specific metabolic reprogramming and oncogenic signaling in the development of colorectal cancer. FA2H is highly expressed in normal colorectal tissues. Assessments through deciphering both published high-throughput data and curated human colorectal cancer samples revealed significant suppression of FA2H in tumors, which is correlated with unfavorable prognosis. Experiments with multiple models of genetic manipulation or treatment with an enzymatic product of FA2H, (R)-2-hydroxy palmitic acid, demonstrated that FA 2-hydroxylation inhibits colorectal cancer cell proliferation, migration, epithelial-to-mesenchymal transition progression, and tumor growth. Bioinformatics analysis suggested that FA2H functions through AMP-activated protein kinase/Yes-associated protein (AMPK/YAP) pathway, which was confirmed in colorectal cancer cells, as well as in tumors. Lipidomics analysis revealed an accumulation of polyunsaturated fatty acids in cells with FA2H overexpression, which may contribute to the observed nutrient deficiency and AMPK activation. Collectively, these data demonstrate that FA 2-hydroxylation initiates a metabolic signaling cascade to suppress colorectal tumor growth and metastasis via the YAP transcriptional axis and provides a strategy to improve colorectal cancer treatment. SIGNIFICANCE: These findings identify a novel metabolic mechanism regulating the tumor suppressor function of FA 2-hydroxylation in colorectal cancer.

The Patatin-Like Phospholipase Domain Containing Protein 7 Facilitates VLDL Secretion by Modulating ApoE Stability.

BACKGROUND AND AIMS: The regulation of hepatic very-low-density lipoprotein (VLDL) secretion is vital for lipid metabolism whose pathogenetic status is involved in fatty liver disease and dyslipidemia seen in hepatic steatosis. Accumulated evidence suggest that apolipoprotein E (ApoE) is closely related to hepatic VLDL secretion. Here, we report that the expression of patatin-like phospholipase domain containing protein 7 (PNPLA7) is strongly induced by hepatic steatosis and positively correlates with plasma triacylglycerol (TAG) levels in the human subjects, whereas the role of PNPLA7 in hepatic VLDL secretion is unknown. APPROACH AND RESULTS: Herein, with genetic manipulation in the mice, the deficiency of hepatic PNPLA7 expression resulted in reduced VLDL secretion accompanied by enhanced hepatic lipid accumulation and decreased hepatic ApoE expression. Furthermore, knockdown of PNPLA7 in the livers of the db/db mice also resulted in significant reduction in plasma TAG level but aggravated hepatic steatosis. Importantly, we observed that PNPLA7 interacted with ApoE and presumably at the site of endoplasmic reticulum. Mechanistically, we have shown that PNPLA7 could modulate polyubiquitination and proteasomal-mediated degradation of ApoE. Overexpressed ApoE restored the impaired VLDL-TAG metabolism in PNPLA7-knockdown primary hepatocytes. CONCLUSION: PNPLA7 plays a critical role in regulating hepatic VLDL secretion by modulating ApoE stability through its interaction with ApoE.

Fatty acid 2-hydroxylation inhibits tumor growth and increases sensitivity to cisplatin in gastric cancer.

BACKGROUND: Most gastric cancers are diagnosed at an advanced or metastatic stage with poor prognosis and survival rate. Fatty acid 2-hydroxylase (FA2H) with high expression in stomach generates chiral (R)-2-hydroxy FAs ((R)-2-OHFAs) and regulates glucose utilization which is important for cell proliferation and invasiveness. We hypothesized that FA2H impacts gastric tumor growth and could represent a novel target to improve gastric cancer therapy. METHODS: FA2H level in 117 human gastric tumors and its association with tumor growth, metastasis and overall survival were examined. Its roles and potential mechanisms in regulating tumor growth were studied by genetic and pharmacological manipulation of gastric cancer cells in vitro and in vivo. FINDINGS: FA2H level was lower in gastric tumor tissues as compared to surrounding tissues and associated with clinicopathologic status of patients, which were confirmed by analyses of multiple published datasets. FA2H depletion decreased tumor chemosensitivity, partially due to inhibition of AMPK and activation of the mTOR/S6K1/Gli1 pathway. Conversely, FA2H overexpression or treatment with (R)-2-OHFAs had the opposite effects. In line with these in vitro observations, FA2H knockdown promoted tumor growth with increased level of tumor Gli1 in vivo. Moreover, (R)-2-OHFA treatment significantly decreased Gli1 level in gastric tumors and enhanced tumor chemosensitivity to cisplatin, while alleviating the chemotherapy-induced weight loss in mice. INTERPRETATION: Our results demonstrate that FA2H plays an important role in regulating Hh signaling and gastric tumor growth and suggest that (R)-2-OHFAs could be effective as nontoxic wide-spectrum drugs to promote chemosensitivity. FUND: Grants of NSF, NIH, and PAPD.

Glomerular Parietal Epithelial Cells Infection Is Associated With Poor Graft Outcome in Kidney Transplant Recipients With BK Polyomavirus-Associated Nephropathy.

BACKGROUND: The purpose of this study was to investigate the effect of BK polyomavirus (BKPyV infection of glomerular parietal epithelial cells (GPECs) on graft outcome in kidney transplant recipients with BKPyV-associated nephropathy (BKPyVAN). METHODS: A total of 152 kidney transplant recipients with BKPyVAN were divided into 31 with (GPEC-positive group) and 121 without (GPEC-negative group) BKPyV-infected GPECs. Clinicopathological characteristics and allograft survival were compared between the groups. RESULTS: The GPEC-positive group had more patients with advanced-stage BKPyVAN than the GPEC-negative group (P < .001). At the last follow-up, the GPEC-positive group had a significantly higher serum creatinine level than the GPEC-negative group. The graft loss rate in the GPEC-positive group was higher than that in the GPEC-negative group (32.3% vs 12.4%; P = .008). Kaplan-Meier analysis showed that the graft survival rate in the GPEC-positive group was lower than that in the GPEC-negative group (log-rank test, P = .004). Multivariate Cox regression analysis demonstrated that BKPyV infection of GPECs was an independent risk factor for graft survival (hazard ratio, 3.54; 95% confidence interval, 1.43-8.76; P = .006). CONCLUSIONS: GPEC infection in patients with BKPyVAN indicates more-severe pathological damage and a rapid decline in renal function. BKPyV infection of GPECs is an independent risk factor for allograft loss.

En bloc kidney transplantation from infant donors younger than 10 months into pediatric recipients.

Early graft loss and poor graft function limit the use of kidneys from infant donors. Six en bloc kidney transplantations were performed from infant donors younger than 10 months into pediatric recipients between November 2012 and September 2015 at our center. We retrospectively analyzed recipient and donor demographics, surgery procedures, complications, graft function and size, and patient and graft survival with a follow-up of 6-39 months (median 15.5 months). Donor age ranged from 1 to 10 months with weight ranging from 3.5 to 10 kg. Recipient age ranged from 10 to 16 years with weight ranging from 30 to 39 kg. One kidney was removed due to arterial thrombosis during surgery, while the other kidney of this en bloc graft remained viable. Urine leak followed by bilateral ureteral obstruction occurred in one recipient. All of the recipients showed immediate graft function. The size of the en bloc kidney increased from 4.2±0.6 cm to 7.6±0.6 cm 6 months after surgery. Patient and graft survival were both 100% at the last follow-up. Our results show that en bloc kidney transplantation from infant donors younger than 10 months into pediatric recipients is effective under the condition of experienced surgical techniques and perioperative management.

Major role of adipocyte prostaglandin E2 in lipolysis-induced macrophage recruitment.

Obesity induces accumulation of adipose tissue macrophages (ATMs), which contribute to both local and systemic inflammation and modulate insulin sensitivity. Adipocyte lipolysis during fasting and weight loss also leads to ATM accumulation, but without proinflammatory activation suggesting distinct mechanisms of ATM recruitment. We examined the possibility that specific lipid mediators with anti-inflammatory properties are released from adipocytes undergoing lipolysis to induce macrophage migration. In the present study, we showed that conditioned medium (CM) from adipocytes treated with forskolin to stimulate lipolysis can induce migration of RAW 264.7 macrophages. In addition to FFAs, lipolytic stimulation increased release of prostaglandin E2(PGE2) and prostaglandin D2(PGD2), reflecting cytosolic phospholipase A2α activation and enhanced cyclooxygenase (COX) 2 expression. Reconstituted medium with the anti-inflammatory PGE2potently induced macrophage migration while different FFAs and PGD2had modest effects. The ability of CM to induce macrophage migration was abolished by treating adipocytes with the COX2 inhibitor sc236 or by treating macrophages with the prostaglandin E receptor 4 antagonist AH23848. In fasted mice, macrophage accumulation in adipose tissue coincided with increases of PGE2levels and COX1 expression. Collectively, our data show that adipocyte-originated PGE2with inflammation suppressive properties plays a significant role in mediating ATM accumulation during lipolysis.

Factors Influencing Graft Outcomes Following Diagnosis of Polyomavirus -Associated Nephropathy after Renal Transplantation.

BACKGROUND: Polyomavirus associated nephropathy (PVAN) is a significant cause of early allograft loss and the course is difficult to predict. The aim of this study is to identify factors influencing outcome for PVAN. METHODS: Between 2006 and 2014, we diagnosed PVAN in 48 (7.8%) of 615 patients monitored for BK virus every 1-4 weeks after modification of maintenance immunosuppression. Logistic or Cox regression analysis were performed to determine which risk factors independently affected clinical outcome and graft loss respectively. RESULTS: After 32.1±26.4 months follow-up, the frequencies of any graft functional decline at 1 year post-diagnosis, graft loss and any graft functional decline at the last available follow-up were 27.1% (13/48), 25.0% (12/48), and 33.3% (16/48), respectively. The 1, 3, 5 year graft survival rates were 100%, 80.5% and 69.1%, respectively. The mean level of serum creatinine at 1 year post-diagnosis and long-term graft survival rates were the worst in class C (p<0.05). Thirty-eight of 46 (82.6%) BKV DNAuria patients reduced viral load by 90% with a median time of 2.75 months (range, 0.25-34.0 months) and showed better graft survival rates than the 8 patients (17.4%) without viral load reduction (p<0.001). Multivariate logistic regression analysis showed that extensive interstitial inflammation (OR 20.2, p = 0.042) and delayed fall in urinary viral load (>2.75 months for >90% decrease) in urine (OR 16.7, p = 0.055) correlated with worse creatinine at 1 year post-diagnosis. Multivariate Cox regression analysis showed that extensive interstitial inflammation (HR 46988, p = 0.032) at diagnosis, and high PVAN stage (HR 162.2, p = 0.021) were associated with worse long-term graft survival rates. CONCLUSIONS: The extent of interstitial inflammation influences short and long-term graft outcomes in patients with PVAN. The degree of PVAN, rate of reduction in viral load, and viral clearance also can be used as prognostic markers in PVAN.

Magnesium sulfate induced toxicity in vitro in AGS gastric adenocarcinoma cells and in vivo in mouse gastric mucosa.

Magnesium sulfate is widely used as a food additive and as an orally administered medication. The aim of this study was to evaluate the possible cytotoxicity of magnesium sulfate on AGS human gastric adenocarcinoma cells and gastric mucosa in mice. A trypan blue exclusion assay was used to determine the reduction in viability of AGS cells exposed to magnesium sulfate, and then effects on cell proliferation were quantified. The role of magnesium sulfate-mediated pro-inflammatory cytokine production in AGS cells was also investigated. mRNA expression for IL-1ß, IL-6, IL-8, and TNF-α was determined by RT-PCR, and secretion of these cytokines was measured by ELISA. Immunohistochemical evaluation of IL-1ß, IL-6, and TNF-α expression was conducted in mouse gastric mucosa. Addition of 3 to 50 mM magnesium sulfate to AGS cells inhibited both cell proliferation and cell viability in a dose-dependent manner. Magnesium sulfate had little effect on production of IL-1ß or IL-6 but significantly inhibited production of IL-8. The animal model demonstrated that magnesium sulfate induced production of IL-1ß, IL-6, and TNF-α. These preliminary data suggest that magnesium sulfate had a direct effect on the stomach and initiates cytotoxicity in moderate concentrations and time periods by inhibiting viability and proliferation of AGS cells and by regulating expression and/or release of pro-inflammatory cytokines.

Monitoring of polyomavirus BK replication and impact of preemptive immunosuppression reduction in renal-transplant recipients in China: a 5-year single-center analysis.

This provides the long-term patient/graft survival and outcome of BK viremia and BK virus allograft nephropathy (BKVAN) in renal transplant recipients in the setting of intensive monitoring and preemptive of reduction of immunosuppression. Quantitative BKV DNA PCR and urinary cytology surveillance were performed regularly after transplantation in 229 kidney recipients. Patients with BK viremia and BKVAN were treated with 30-50% reduction in doses of tacrolimus and/or mycophenolate mofetil and were monitored for BKV every 3-6 months. All the patients were followed for 5 years. Overall 5-year patient and graft survival were 95.6% and 92.1%, respectively, and independent of presence of decoy cells, BK viruria, viremia, or BKVAN. After reduction of immunosuppression, BK viremia (n = 38) resolved in 100% of patients, without increased acute rejection. Recurrent BK viremia was not observed in viremic patients without BKVAN (n = 30). All BKVAN patients (n = 7, 3.1%) cleared viremia with a mean time of 5.9 months (range 1-15 months) and manifested no decline in estimated glomerular filtration rate from 1 month to 5 years after transplantation. Viral monitoring and preemptive reduction of immunosuppression resulted in the successful resolution of BK viremia and BKVAN with excellent graft survival and renal function at 5 years.

Regulation of AMPK activation by CD36 links fatty acid uptake to ß-oxidation.

Increases in muscle energy needs activate AMPK and induce sarcolemmal recruitment of the fatty acid (FA) translocase CD36. The resulting rises in FA uptake and FA oxidation are tightly correlated, suggesting coordinated regulation. We explored the possibility that membrane CD36 signaling might influence AMPK activation. We show, using several cell types, including myocytes, that CD36 expression suppresses AMPK, keeping it quiescent, while it mediates AMPK activation by FA. These dual effects reflect the presence of CD36 in a protein complex with the AMPK kinase LKB1 (liver kinase B1) and the src kinase Fyn. This complex promotes Fyn phosphorylation of LKB1 and its nuclear sequestration, hindering LKB1 activation of AMPK. FA interaction with CD36 dissociates Fyn from the protein complex, allowing LKB1 to remain cytosolic and activate AMPK. Consistent with this, CD36(-/-) mice have constitutively active muscle and heart AMPK and enhanced FA oxidation of endogenous triglyceride stores. The molecular mechanism described, whereby CD36 suppresses AMPK, with FA binding to CD36 releasing this suppression, couples AMPK activation to FA availability and would be important for the maintenance of cellular FA homeostasis. Its dysfunction might contribute to the reported association of CD36 variants with metabolic complications of obesity in humans.

Adipose tissue monomethyl branched-chain fatty acids and insulin sensitivity: Effects of obesity and weight loss.

OBJECTIVES: An increase in circulating branched-chain amino acids (BCAA) is associated with insulin resistance. Adipose tissue is a potentially important site for BCAA metabolism. It was evaluated whether monomethyl branched-chain fatty acids (mmBCFA) in adipose tissue, which are likely derived from BCAA catabolism, are associated with insulin sensitivity. METHODS: Insulin-stimulated glucose disposal was determined by using the hyperinsulinemic-euglycemic clamp procedure with stable isotope glucose tracer infusion in nine lean and nine obese subjects, and in a separate group of nine obese subjects before and 1 year after Roux-en-Y gastric bypass (RYGB) surgery (38% weight loss). Adipose tissue mmBCFA content was measured in tissue biopsies taken in the basal state. RESULTS: Total adipose tissue mmBCFA content was ∼30% lower in obese than lean subjects (P=0.02) and increased by ∼65% after weight loss in the RYGB group (P=0.01). Adipose tissue mmBCFA content correlated positively with skeletal muscle insulin sensitivity (R(2) =35%, P=0.01, n=18). CONCLUSIONS: These results demonstrate a novel association between adipose tissue mmBCFA content and obesity-related insulin resistance. Additional studies are needed to determine whether the association between adipose tissue mmBCFA and muscle insulin sensitivity is causal or a simple association.

The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis.

Brown fat activates uncoupled respiration in response to cold temperature and contributes to systemic metabolic homeostasis. To date, the metabolic action of brown fat has been primarily attributed to its role in fuel oxidation and uncoupling protein 1 (UCP1)-mediated thermogenesis. Whether brown fat engages other tissues through secreted factors remains largely unexplored. Here we show that neuregulin 4 (Nrg4), a member of the epidermal growth factor (EGF) family of extracellular ligands, is highly expressed in adipose tissues, enriched in brown fat and markedly increased during brown adipocyte differentiation. Adipose tissue Nrg4 expression was reduced in rodent and human obesity. Gain- and loss-of-function studies in mice demonstrated that Nrg4 protects against diet-induced insulin resistance and hepatic steatosis through attenuating hepatic lipogenic signaling. Mechanistically, Nrg4 activates ErbB3 and ErbB4 signaling in hepatocytes and negatively regulates de novo lipogenesis mediated by LXR and SREBP1c in a cell-autonomous manner. These results establish Nrg4 as a brown fat-enriched endocrine factor with therapeutic potential for the treatment of obesity-associated disorders, including type 2 diabetes and nonalcoholic fatty liver disease (NAFLD).

Mortality of urinary tract cancer in Inner Mongolia 2008- 2012.

The aim of this study was to determine the mortality rate and burden of urinary tract cancers among residents of Inner Mongolia. We analyzed mortality data reported by the Death Registry System from 2008 to 2012. The rate of mortality due to urinary tract cancer was 2.04 per 100,000 person-years for the total population, 2.91 for men, and 1.11 for women. Therefore, the mortality rate for men was 2.62-fold the mortality rate for women, constituting a statistically significant difference (p<0.001). Over the period 2008 through 2012, the total potential years of life lost was 1388.1 person-years for men and 777.1 person-years for women, and the average years of life lost were 7.71 years per male decedent and 12.0 years per female decedent. Mortality due to urinary tract cancers is substantially greater among the elderly population. Further, the mortality rate associated with urinary tract cancers is greater for elderly men than it is for elderly women. Therefore, in Inner Mongolia, urinary tract cancers appear to pose a greater mortality risk for men than they do for women.

The gap in digestive organ cancers in Inner Mongolia, 2009-2012.

OBJECTIVES: The aim of this study was to explore the characteristics of digestive organ cancer mortality and the potential years of life lost in Inner Mongolia, and to provide evidence for the prevention of digestive organ cancers. METHODS: Using data from the Death Registry System from 2009 to 2012, we classified male and female cancer deaths according to the International Classification of Disease (10th revision). The mortality and potential years of life lost were calculated for digestive organ cancers in Inner Mongolia. The average years of life lost was calculated. RESULTS: Digestive organ cancer mortality in Inner Mongolia was higher in men than in women. The potential years of life lost were also much higher in men than in women. Gallbladder cancer, pancreatic cancer, and colorectal, anus, and anal canal cancer were the most prominent contributors to mortality. Esophageal cancer was the most prominent contributor to potential years of life lost, and was the leading cause of average years of life lost in both sexes. CONCLUSION: Liver cancer and stomach cancer mortality and the potential years of life lost to liver and stomach cancer are demonstrably higher in Inner Mongolia. Although esophageal cancer mortality was not the highest of the digestive organ cancers, the average years of life lost to esophageal was the highest for both sexes, and it should therefore be targeted for prevention.

Deficiency of liver Comparative Gene Identification-58 causes steatohepatitis and fibrosis in mice.

Triglyceride (TG) accumulation in hepatocytes (hepatic steatosis) preludes the development of advanced nonalcoholic fatty liver diseases (NAFLDs) such as steatohepatitis, fibrosis, and cirrhosis. Mutations in human Comparative Gene Identification-58 (CGI-58) cause cytosolic TG-rich lipid droplets to accumulate in almost all cell types including hepatocytes. However, it is unclear if CGI-58 mutation causes hepatic steatosis locally or via altering lipid metabolism in other tissues. To directly address this question, we created liver-specific CGI-58 knockout (LivKO) mice. LivKO mice on standard chow diet displayed microvesicular and macrovesicular panlobular steatosis, and progressed to advanced NAFLD stages over time, including lobular inflammation and centrilobular fibrosis. Compared with CGI-58 floxed control littermates, LivKO mice showed 8-fold and 52-fold increases in hepatic TG content, which was associated with 40% and 58% decreases in hepatic TG hydrolase activity at 16 and 42 weeks, respectively. Hepatic cholesterol also increased significantly in LivKO mice. At 42 weeks, LivKO mice showed increased hepatic oxidative stress, plasma aminotransferases, and hepatic mRNAs for genes involved in fibrosis and inflammation, such as α-smooth muscle actin, collagen type 1 α1, tumor necrosis factor α, and interleukin-1ß. In conclusion, CGI-58 deficiency in the liver directly causes not only hepatic steatosis but also steatohepatitis and fibrosis.

Ubiquitination and degradation of the hominoid-specific oncoprotein TBC1D3 is regulated by protein palmitoylation.

Expression of the hominoid-specific oncoprotein TBC1D3 promotes enhanced cell growth and proliferation by increased activation of signal transduction through several growth factors. Recently we documented the role of CUL7 E3 ligase in growth factors-induced ubiquitination and degradation of TBC1D3. Here we expanded our study to discover additional molecular mechanisms that control TBC1D3 protein turnover. We report that TBC1D3 is palmitoylated on two cysteine residues: 318 and 325. The expression of double palmitoylation mutant TBC1D3:C318/325S resulted in protein mislocalization and enhanced growth factors-induced TBC1D3 degradation. Moreover, ubiquitination of TBC1D3 via CUL7 E3 ligase complex was increased by mutating the palmitoylation sites, suggesting that depalmitoylation of TBC1D3 makes the protein more available for ubiquitination and degradation. The results reported here provide novel insights into the molecular mechanisms that govern TBC1D3 protein degradation. Dysregulation of these mechanisms in vivo could potentially result in aberrant TBC1D3 expression and promote oncogenesis.